EP2712858A1

EP2712858A1 - Process for producing thionocarboxylic acid ester

Info

Publication number: EP2712858A1
Application number: EP13184535.6A
Authority: EP
Inventors: Takashi Namikawa; Yousuke Kishikawa; Takashi Nomura; Asako Tanaka; Kenji Adachi
Original assignee: Daikin Industries Ltd
Current assignee: Daikin Industries Ltd
Priority date: 2012-09-27
Filing date: 2013-09-16
Publication date: 2014-04-02
Anticipated expiration: 2033-09-16
Also published as: CN103694154B; JP2014065693A; KR20140041353A; CN103694154A; JP5737255B2; EP2712858B1; KR101546144B1

Abstract

The present invention provides a process comprising reacting a halogenated thiocarbonyl compound represented by Formula (1):

wherein Ar is an optionally substituted aryl group and X is a halogen atom, with an Grignard compound represented by Formula (2): R-MgY wherein R is an optionally substituted aryl group or an optionally substituted cycloalkyl group and Y is a halogen atom. This process can produce the desired arylthionocarboxylic acid ester represented by Formula (3): wherein Ar and R are as defined above, in a high yield under relatively mild reaction conditions.

Description

Technical Field

The present invention relates to a process for producing an ester of aryl-containing thionocarboxylic acid that is useful as a liquid crystal material, etc.

Background Art

The aryl ester of arylthionocarboxylic acid represented by the formula R¹C=(S)OR², wherein R¹ and R² independently represent an optionally substituted aryl group, is a compound that is useful as a liquid crystal material, etc.
Various methods are known as methods for producing thionocarboxylic acid esters having this structure. Examples of such methods include a method comprising reacting a chlorothionoformic acid ester with an aromatic compound (Non-patent Literature (NPL) 1); a method comprising treating a carbanion with a dithiocarbonic acid ester or a thionocarbonic acid ester (Non-patent Literature (NPL) 2); a method comprising reacting an orthoester with hydrogen sulfide (Non-patent Literature (NPL) 3); a method comprising reacting a carboxylic acid ester with phosphorus pentasulfide or Lawesson's reagent (Non-patent Literature (NPL) 4); a method comprising reacting a thionocarboxylic acid chloride with an alcohol or phenol (Non-patent Literature (NPL) 5); a method comprising reacting a nitrile with an alcohol and then reacting the resulting product with hydrogen sulfide (Non-patent Literature (NPL) 6); a method comprising treating a methylated aromatic compound with sulfur and an alcohol (Non-patent Literature (NPL) 7); and a method comprising reacting a thioacyl disulfide with an alcoholate (Non-patent Literature (NPL) 8).
However, among these methods, the methods disclosed in NPL 1, 2, 4, 7, etc., are low-yield; in particular, the method disclosed in NPL 4 requires a high temperature of 100°C or more for the reaction, and also has a drawback of generating a large amount of by-products; therefore, these methods cannot be regarded as efficient methods.
The methods disclosed in NPL 3 and 6 use hydrogen sulfide, which is so toxic that its handling requires specialized equipment; therefore, these methods are unsuitable as industrial processes for production. Further, the method disclosed in NPL 5 cannot be regarded as a comprehensively superior method due to a low synthesis yield of the starting thionocarboxylic acid chloride. The method disclosed in NPL 8 comprises a large number of steps, including synthesizing a thioacyl disulfide from a dithiocarboxylic acid derivative and then reacting the thioacyl disulfide with an alcoholate; therefore, this method cannot be regarded as a convenient method.

Citation List

Non-patent Literature

NPL 1:: H. Viola, et al., Chem. Ber., 101, 3517 (1968)
NPL 2:: Liebigs Ann. Chem., 1973, 1637
NPL 3:: A. Ohno et al., Tetrahedron Lett., 1968, 2083
NPL 4:: Synthesis, 1973, 149; Bull. Chem. Soc. Belg., 87, 293 (1987)
NPL 5:: S. Scheithauer et al., Chem. Ber., 98, 838 (1965)
NPL 6:: Liebigs Ann. Chem., 1974, 671
NPL 7:: Z. Chem., 6, 108 (1966)
NPL 8:: K.A. Latif et al., Tetrahedron, 26, 4247 (1970)

Summary of Invention

Technical Problem

The present invention was made in view of the above-mentioned problems in the prior art. A primary object of the invention is to provide a relatively convenient and industrially advantageous process for producing, in a high yield, an arylthionocarboxylic acid ester, which is useful as a liquid crystal material, etc.

Summary of Invention

Technical Problem

Solution to Problem

To achieve the above object, the present inventors conducted extensive research. As a result, the inventors found that when a halogenated thiocarbonyl compound is used as a starting material and reacted with a Grignard compound having an aryl group or a cycloalkyl group, the desired arylthionocarboxylic acid ester can be produced in a high yield under mild reaction conditions using relatively safe starting materials. The present invention has been accomplished based on this finding. More specifically, the present invention provides the following processes for producing an arylthionocarboxylic acid ester.
Item 1. A process for producing an arylthionocarboxylic acid ester represented by Formula (3):
wherein Ar is an optionally substituted aryl group and R is an optionally substituted aryl group or an optionally substituted cycloalkyl group;
the process comprising reacting a halogenated thiocarbonyl compound represented by Formula (1):
wherein Ar is as defined above and X is a halogen atom, with a Grignard compound represented by Formula (2): R-MgY wherein R is as defined above and Y is a halogen atom.
Item 2. The process according to Item 1, wherein the reaction is performed in an aprotic organic solvent.
Item 3. The process according to Item 1 or 2, wherein the halogenated thiocarbonyl compound represented by Formula (1) is reacted with the Grignard compound represented by Formula (2) in the presence of at least one component selected from the group consisting of trivalent iron compounds, monovalent copper compounds, divalent copper compounds, divalent nickel compounds, divalent zinc compounds, and divalent cobalt compounds.
Item 4. A process for producing an arylthionocarboxylic acid ester represented by Formula (3):
wherein Ar is an optionally substituted aryl group and R is an optionally substituted aryl group or an optionally substituted cycloalkyl group;
the process comprising reacting a halide represented by Formula (4): R-Y wherein R is as defined above and Y is a halogen atom, with a magnesium compound, and then reacting the reaction product with a halogenated thiocarbonyl compound represented by Formula (1):
wherein Ar is as defined above and X is a halogen atom.
Item 5. The process according to Item 4, wherein the reaction with the halogenated thiocarbonyl compound represented by Formula (1) is performed in the presence of at least one component selected from the group consisting of trivalent iron compounds, monovalent copper compounds, divalent copper compounds, divalent nickel compounds, divalent zinc compounds, and divalent cobalt compounds.
The process of the present invention for producing an arylthionocarboxylic acid ester is explained in more detail below.
The process of the present invention for producing an arylthionocarboxylic acid ester comprises reacting a halogenated thiocarbonyl compound represented by Formula (1):
wherein Ar is an optionally substituted aryl group and X is a halogen atom, with a Grignard compound represented by Formula (2): R-MgY wherein R is an optionally substituted aryl group or an optionally substituted cycloalkyl group and Y is a halogen atom. This process can produce an arylthionocarboxylic acid ester represented by Formula (3):
wherein Ar and R are as defined above, in a high yield under relatively mild conditions.
First, the starting compounds used in the production process of the present invention are explained in more detail.

Starting compounds

(1) Halogenated thiocarbonyl compound

In the starting halogenated thiocarbonyl compound represented by Formula (1), Ar is an optionally substituted aryl group. Examples of optionally substituted aryl groups include optionally substituted phenyl, optionally substituted naphthyl, and the like.
There is no particular limitation on the substituent on the aryl group, insofar as the substituent is inert to the reaction with a Grignard compound represented by Formula (2): R-MgY described below. Specific examples of such substituents include alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, cyano, aryl, halogen, and the like. Among these, examples of alkyl groups include linear or branched lower alkyl groups having about 1 to 5 carbon atoms; and examples of fluoroalkyl groups include linear or branched lower alkyl groups having about 1 to 5 carbon atoms in which hydrogen atoms are partially or completely replaced by fluorine. Examples of alkoxy groups include linear or branched lower alkoxy groups having about 1 to 5 carbon atoms. Examples of fluoroalkoxy groups include linear or branched lower alkoxy groups having about 1 to 5 carbon atoms in which hydrogen atoms are partially or completely replaced by fluorine. Examples of aryl groups as substituents include phenyl, naphthyl, and the like. The substituent aryl groups may further contain a substituent that is inert to the reaction. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.
In the above Formula (1), the halogen atom represented by X may be, for example, fluorine, chlorine, bromine, or iodine. Chlorine is particularly preferable.

(2) Grignard compound

In the Grignard compound represented by Formula (2): R-MgY wherein R is an optionally substituted aryl group or an optionally substituted cycloaryl group and Y is a halogen atom, the optionally substituted aryl group represented by R may be, for example, an optionally substituted phenyl group or an optionally substituted naphthyl group. The substituent on the aryl group may be any substituent that is inert to the reaction with a halogenated thiocarbonyl compound represented by Formula (1), and that is also inert to the reaction for producing a Grignard compound represented by Formula (2): R-MgY from a halide represented by Formula (4): R-Y described below. Specific examples of such substituents may be the same as the aforementioned examples of substituents on the aryl group represented by Ar.
The cycloalkyl group of the optionally substituted cycloalkyl group represented by R may be, for example, a cycloalkyl group having about 3 to 8 carbon atoms, and preferably about 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The substituent on the cycloalkyl group may be any substituent that is inert to the reaction with a halogenated thiocarbonyl compound represented by Formula (1), and that is also inert to the reaction for producing a Grignard compound represented by Formula (2): R-MgY from a halide represented by Formula (4): R-Y described below. Specific examples of such substituents include alkyl, cycloalkyl, fluoroalkyl, and the like. Among such substituents, examples of alkyl groups include linear or branched lower alkyl groups having about 1 to 5 carbon atoms; and examples of fluoroalkyl groups include linear or branched lower alkyl groups having about 1 to 5 carbon atoms in which hydrogen atoms are partially or completely replaced by fluorine. Examples of cycloaryl groups as substituents include cycloalkyl groups having about 3 to 8 carbon atoms. The substituent cycloaryl groups may further contain a substituent that is inert to the reaction, such as alkyl.
To obtain a Grignard compound represented by Formula (2): R-MgY, for example, a halide represented by Formula (4): R-Y may be reacted with a magnesium compound.
The magnesium compound that can be used in this reaction is not particularly limited insofar as the compound is reactive with a halide represented by Formula (4) to produce a Grignard compound. Specific examples of such magnesium compounds include metal magnesium, i-PrMgCl (isopropylmagnesium chloride), i-PrMgBr (isopropylmagnesium bromide), and an i-PrBu₂MgLi ate complex which can be produced from n-BuLi and i-PrMgCl or i-PrMgBr.
The amount of the magnesium compound may be about 1.0 to 10.0 mol, and preferably about 1.0 to 2.0 mol, per mol of the halide represented by Formula (4): R-Y.
Typically, the reaction of a halide represented by Formula (4): R-Y with a magnesium compound is preferably performed in an aprotic organic solvent inert to the reaction. Examples of aprotic organic solvents include tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, dibutyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, dioxane, benzene, toluene, xylene, pentane, hexane, heptane, and the like. Such aprotic organic solvents may be used as a mixture of two or more, if necessary.
There is no particular limitation on the concentrations of the starting materials in the reaction solvent. For example, the concentration of the halide represented by Formula (4): R-Y may be about 0.5 to 10.0 mol/L.
The temperature at which the reaction of a halide represented by Formula (4): R-Y with a magnesium compound is performed is preferably about 0 to 100°C, and more preferably about 20 to 70°C.
The pressure during the reaction is not particularly limited, and can typically be performed under atmospheric pressure. The atmosphere during the reaction is not particularly limited. Typically, the reaction is preferably performed in an inert gas atmosphere, such as a nitrogen atmosphere or an argon atmosphere. Typically, the reaction time may be about 30 minutes to about 10 hours.
The yield of the Grignard compound represented by Formula (2): R-MgY can be increased by reacting a halide represented by Formula (4): R-Y with a magnesium compound in the presence of LiCl, iodine, dibromoethane, or the like ingredients. The total amount of these ingredients is preferably about 1.0 to 5.0 mol, and more preferably about 1.0 to 1.2 mol, per mol of the halide represented by Formula (4): R-Y.
The above process can produce a Grignard compound represented by Formula (2): R-MgY wherein R is an optionally substituted aryl group or an optionally substituted cycloalkyl group and Y is a halogen atom.

Process for producing an arylthionocarboxylic acid ester

As described above, the desired arylthionocarboxylic acid ester of the present invention, which is represented by Formula (3):
wherein Ar is an optionally substituted aryl group and R is an optionally substituted aryl group or an optionally substituted cycloalkyl group, can be obtained by reacting a halogenated thiocarbonyl compound represented by Formula (1):
wherein Ar is as defined above and X is a halogen atom, with a Grignard compound represented by Formula (2): R-MgY wherein R is as defined above and Y is a halogen atom.
The amount of the Grignard compound represented by Formula (2): R-MgY wherein R and Y are as defined above may be about 0.8 to 2.0 mol, and preferably about 0.9 to 1.2 mol, per mol of the halogenated thiocarbonyl compound represented by Formula (1).
The reaction of a halogenated thiocarbonyl compound represented by Formula (1) with a Grignard compound represented by Formula (2): R-MgY is preferably performed in an aprotic organic solvent. Examples of usable aprotic organic solvents may be the same as the aforementioned examples of solvents that can be used in the reaction of a halide represented by Formula (4): R-Y with a magnesium compound.
There is no particular limitation on the concentrations of the starting materials in the reaction solvent. For example, the concentration of the halogenated thiocarbonyl compound represented by Formula (1) may be about 0.1 mol/L to 3.0 mol/L. The temperature at which the reaction of a halogenated thiocarbonyl compound with a Grignard compound is performed is such that when using a Grignard compound wherein R is an optionally substituted aryl group, the temperature is preferably about -78 to 25°C, and more preferably about -50 to 0°C: and when using a Grignard compound wherein R is an optionally substituted cycloalkyl group, the temperature is preferably about -78 to 0°C, and more preferably about -78 to -30°C.
The pressure during the reaction is not particularly limited. The reaction can typically be performed under atmospheric pressure. The atmosphere during the reaction is not particularly limited. Typically, the reaction is preferably performed in an inert gas atmosphere, such as a nitrogen atmosphere or an argon atmosphere. Typically, the reaction time may be about 0.5 to 10.0 hours.
In the production process of the present invention, the yield of the desired arylthionocarboxylic acid ester represented by Formula (3) can be increased particularly by reacting a halogenated thiocarbonyl compound represented by Formula (1) with a Grignard compound represented by Formula (2): R-MgY in the presence of a catalyst. Examples of usable catalysts include trivalent iron compounds, monovalent copper compounds, divalent copper compounds, divalent nickel compounds, divalent zinc compounds, divalent cobalt compounds, and the like. Such compounds can be used singly, or as a mixture of two or more. Specific examples of trivalent iron compounds include tris(2,4-pentanedionato)iron(III), ferric chloride, and the like. Examples of monovalent or divalent copper compounds include copper halides such as copper(I) chloride, copper(I) bromide, and copper(I) iodide; copper cyanide (CuCN), cupric chloride, dilithium tetrachlorocuprate(II)(Li₂C_UCl₄), and the like. Examples of divalent nickel compounds include nickel chloride and the like. Examples of divalent zinc compounds include zinc chloride and the like. Examples of divalent cobalt compounds include cobalt chloride and the like.
Such a catalyst is preferably used in an amount of about 0.01 to 2.00 mol, and more preferably 0.01 to 0.10 mol, per mol of the halogenated thiocarbonyl compound represented by Formula (1).
The above process can produce an arylthionocarboxylic acid ester represented by Formula (3):
in a high yield.
The arylthionocarboxylic acid ester obtained by the above process can be purified and collected by a known method, such as silica gel column chromatography or recrystallization.
In the present invention, instead of directly reacting a halogenated thiocarbonyl compound represented by Formula (1):
wherein Ar is an optionally substituted aryl group and X is a halogen atom, with a Grignard compound represented by Formula (2): R-MgY wherein R is an optionally substituted aryl group or an optionally substituted cycloalkyl group and Y is a halogen atom, the following process can also be used to produce the desired arylthionocarboxylic acid ester represented by Formula (3):
wherein Ar and R are as defined above. That is, a halide represented by Formula (4): R-Y, which is a starting material for producing a Grignard compound represented by Formula (2): R-MgY, is reacted with a magnesium compound and then the obtained reaction product is reacted with a halogenated thiocarbonyl compound represented by Formula (1):
wherein Ar is an optionally substituted aryl group and X is a halogen atom. This method can produce the desired arylthionocarboxylic acid ester represented by Formula (3) in a high yield in a continuous process without separating a Grignard compound represented by Formula (2): R-MgY, which is an intermediate product. The reaction conditions in the step of reacting a halide represented by Formula (4) with a magnesium compound and in the step of reacting the reaction product with a halogenated thiocarbonyl compound represented by Formula (1) in the continuous process may be the same as the aforementioned conditions in each reaction step.
The arylthionocarboxylic acid ester obtained by this process can be purified and collected by a known method, such as silica gel column chromatography or recrystallization.

Advantageous Effects of Invention

According to the present invention, the desired arylthionocarboxylic acid ester can be obtained in a high yield by using relatively inexpensive and highly safe starting materials under mild reaction conditions.

Description of Embodiments

The present invention is explained in more detail below with reference to Examples.

Example 1

Magnesium (1.6 g, 64.0 mmol), LiCl (2.7 g, 64.0 mmol), and tetrahydrofuran (hereinafter abbreviated as "THF") (10.0 mL) were added in a nitrogen atmosphere to a 50 ml three-necked flask equipped with a stirring bar and a thermometer. After chlorobenzene (7.2 g, 64 mmol) was added, the mixture was stirred at room temperature for 2 hours to produce a Grignard compound. Subsequently, phenyl chlorothionoformate (11.0 g, 64.0 mmol), tris(2,4-pentanedionato)iron(III) (Fe(acac)₃) (0.7 g, 1.9 mmol), and THF (50.0 mL) were added in a nitrogen atmosphere to a 200 ml three-necked flask equipped with a stirring bar and a thermometer. After the mixture was cooled to -30°C, the Grignard compound obtained by the above process was added, and the resulting mixture was stirred for 2 hours to complete the reaction.
This mixture was returned to room temperature, and extracted with toluene/hydrochloric acid. The organic layer was evaporated under reduced pressure. The obtained solid was purified by silica gel column chromatography to give phenyl thionobenzoate as a yellow solid (11.9 g, 55.5 mmol). The yield was 87%.

Examples 2 to 19

Using the starting materials shown in Tables 1 and 2, the reaction was performed in the same manner as in Example 1. Tables 1 and 2 show the kinds and yields of the obtained products. The each Grignard compound shown in the Compound (2) column of the table was obtained by reacting magnesium with a halide serving as precursor of the each Grignard compound in the same manner as in Example 1. The numerical values shown in the Catalyst column of the table are the amounts of catalyst expressed in mol% relative to Compound (1).

Table 1

Example	Compound (1)	Catalyst	Compound (2)	Solvent	Temp. °C	Product	Yield (%)*
1		Fe(acac)₃ 3mol%		THF	-30°C		87
2		Fe(acac)₃ 3mol%		THF	-30°C		87
3		Fe(acac)₃ 1mol%		THF	-30°C		75*
4		FeCl₃ 3mol%		THF	-30°C		83*
5		NiCl₂(dpp p) 1mol%		THF	-30°C		72*
6		CuCl₃ 100mol%		THF	-30°C		64*
7		CoCl₂ 1mol%		THF	-30°C		23*
8		Li₂CuCl₄ 5mol%		THF	-30°C		68*
9		Fe(acac)₃ 3mol%		THF	-30°C		82*
10		Fe(acac)₃ 3mol%		THF	-30°C		83*

* Determined by ¹⁹F NMR

Table 2

Example	Compound (1)	Catalyst	Compound (2)	Solvent	Temp. °C	Product	Yield (%)*
11		Fe(acac)₃ 3mol%		THF	-30°C		85*
12		Fe(acac)₃ 3mol%		THF	-30°C		78*
13		Fe(acac)₃ 3mol%		THF	-30°C		80*
14		Fe(acac)₃ 3mol%		THF	-30°C		77*
15		Fe(acac)₃ 3mol%		THF	-30°C		75*
16		Fe(acac)₃ 3mol%		THF	-30°C		83
17		Fe(acac)₃ 3mol%		THF	-30°C		82
18		no cat.		THF	-30°C		20
19		Fe(acac)₃ 3mol%		THF	-30°C		45

*Determined by ¹⁹F NMR

Example 20

Magnesium (1.6 g, 64.0 mmol), dibromoethane (0.6 g, 3.2 mmol), and cyclopentyl methyl ether (CPME) (10.0 mL) were added in a nitrogen atmosphere to a 50 ml three-necked flask equipped with a stirring bar and a thermometer. After bromocyclohexane (10.4 g, 64 mmol) was added, the mixture was stirred at 60°C for 1 hour to produce a Grignard compound.
Subsequently, phenyl chlorothionoformate (11.0 g, 64 mmol), a 0.1 M tetrahydrofuran solution of dilithium tetrachlorocuprate(II)(19 mL, 1.9 mmol), and THF (10 mL) were added in a nitrogen atmosphere to a 200 ml three-necked flask equipped with a stirring bar and a thermometer. After the mixture was cooled to -30°C, the Grignard compound obtained by the above process was added, and the resulting mixture was stirred for 2 hours to complete the reaction. This mixture was returned to room temperature, and extracted with toluene/hydrochloric acid. The organic layer was evaporated under reduced pressure. The obtained solid was purified by silica gel column chromatography to give cyclohexyl thionobenzoate as a yellow solid (10.1 g, 46 mmol). The yield was 72%.

Examples 21 to 23

Using the starting materials shown in Table 3, the reaction was performed in the same manner as in Example 20. Table 3 shows the kinds and yields of the obtained products. The each Grignard compound shown in the Compound (2) column of the table was obtained by reacting magnesium with a halide serving as precursor of each Grignard compound in the same manner as in Example 20. Further, the numerical values shown in the Catalyst column of the table are the amounts of catalyst expressed in mol% relative to Compound (1).

Table 3

Example	Compound (1)	Catalyst	Compound (2)	Solvent	Temp. °C	Product	Yield (%)*
20		Li₂CuCl₄ 3mol%		CPME/THF	-30°C		72
21		Li₂CuCl₄ 3mol%		CPME/THF	-30°C		65
22		Li₂CuCl₄ 3mol%		CPME/THF	-30°C		68*
23		Li₂CuCl₄ 3mol%		CPME/THF	-30°C		62

* Determined by ¹⁹F NMR

Claims

A process for producing an arylthionocarboxylic acid ester represented by Formula (3):
wherein Ar is an optionally substituted aryl group and R is an optionally substituted aryl group or an optionally substituted cycloalkyl group;
the process comprising reacting a halogenated thiocarbonyl compound represented by Formula (1):
wherein Ar is as defined above and X is a halogen atom, with a Grignard compound represented by Formula (2): R-MgY wherein R is as defined above and Y is a halogen atom.
The process according to claim 1, wherein the reaction is performed in an aprotic organic solvent.
The process according to claim 1 or 2, wherein the halogenated thiocarbonyl compound represented by Formula (1) is reacted with the Grignard compound represented by Formula (2) in the presence of at least one component selected from the group consisting of trivalent iron compounds, monovalent copper compounds, divalent copper compounds, divalent nickel compounds, divalent zinc compounds, and divalent cobalt compounds.
A process for producing an arylthionocarboxylic acid ester represented by Formula (3):
wherein Ar is an optionally substituted aryl group and R is an optionally substituted aryl group or an optionally substituted cycloalkyl group;
the process comprising reacting a halide represented by Formula (4): R-Y wherein R is as defined above and Y is a halogen atom, with a magnesium compound, and then reacting the reaction product with a halogenated thiocarbonyl compound represented by Formula (1):
wherein Ar is as defined above and X is a halogen atom.
The process according to claim 4, wherein the reaction with the halogenated thiocarbonyl compound represented by Formula (1) is performed in the presence of at least one component selected from the group consisting of trivalent iron compounds, monovalent copper compounds, divalent copper compounds, divalent nickel compounds, divalent zinc compounds, and divalent cobalt compounds.